Cardiac aldosterone production in genetically hypertensive rats.
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Aldosterone is synthesized in extra-adrenal tissues, both blood vessels and brain. We undertook the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibition, and angiotensin II on aldosterone synthesis in the heart. To clarify the pathophysiological role of cardiac aldosterone in the hypertensive heart, we compared the synthesis of aldosterone in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats. The effects of the aldosterone antagonist spironolactone on myocardial hypertrophy in adrenalectomized SHRSP were also studied. Isolated rat hearts were perfused for 2 hours, and the perfusate was analyzed with HPLC and mass spectrometry. The activity of aldosterone synthase was estimated on the basis of the conversion of [(14)C]deoxycorticosterone to [(14)C]aldosterone. The levels of aldosterone synthase gene (CYP11B2) mRNA were determined with competitive polymerase chain reaction. Aldosterone production, the activity of aldosterone synthase, and the expression of CYP11B2 mRNA were increased in hearts from adrenalectomized rats and rats treated with angiotensin II. ACE inhibitors decreased cardiac aldosterone synthesis. Cardiac aldosterone, aldosterone synthase activity, and CYP11B2 mRNA levels in hearts from 2- and 4-week-old SHRSP were significantly greater than those of age-matched Wistar-Kyoto rats. Spironolactone prevented cardiac hypertrophy in adrenalectomized SHRSP. These results suggest that the rat heart produces aldosterone and that endogenous cardiac aldosterone may affect cardiac function and hypertrophy in hypertension in rats. (+info)
Hormone profiles in hormone-dependent cancers.
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Studies on the relationship of urinary excretion of androgen metabolites and estrogens to the natural history of breast cancer are reviewed. The importance of distinguishing between "within-population" studies (i.e., cancer patients versus normal controls) and "between populations" studies (i.e., low-risk versus high-risk populations) is emphasized, and it is pointed out that "qualitative" agreement (i.e. the same direction of differences) between the two types of studies must be present in order to implicate a hormonal parameter as a determinant of the natural history of breast cancer. For reasons detailed in this paper, it is concluded that the reported relationship of low urinary androgen metabolite excretion to increased risk of developing breast cancer and poor response to adrenalectomy or hypophysectomy and the validity of the "estriol hypothesis," namely, that a high urinary ratio of estriol to estrone-plus-estradiol in early life is protective against subsequent development of breast cancer, are both dubious. A new hypothesis concerning the relationship of estrogens to breast cancer risk is presented: "A period of of time, prior to age 30, during which the amount of biological availability of active estrogens' (i.e., estrone and estradiol) is diminished, protects against subsequent development of cancer." This hypothesis is shown to be compatible with the epidemiological and biochemical data. Reports concerning the influence of nutrition on endocrine parameters are reviewed. Inanition and obesity have been shown to alter steroid metabolism but it is not known whether nutritional "microdifferences" (i.e., differences between populations or individuals that are due to cultural, geographic, or socioeconomic factors, but that fall within the range of "normal" or adequate nutrition) can also alter steroid metabolism. (+info)
Corticosteroids regulate 5-HT(1A) but not 5-HT(1B) receptor mRNA in rat hippocampus.
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The role of mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) in the regulation of serotonin receptors has not been clearly delineated. There is no consensus regarding the regulation of 5-HT(1A) receptors, and corticosteroid regulation of 5-HT(1B) mRNA has not been previously studied. We compared the effects of long-term (two week) adrenalectomy (no MR or GR activation) and several hormone replacement protocols designed to stimulate MR selectively (ALDO), MR and GR (HCT), and continuous MR with cyclical GR activation (SHAM adrenalectomy). 5-HT(1A) and 5-HT(1B) mRNAs were measured by in situ hybridization in hippocampus and raphe nuclei. None of the experimental manipulations altered 5-HT(1B) mRNA levels in the hippocampus or dorsal raphe, and also had no effect on 5-HT(1A) mRNA in dorsal or median raphe. However, 5-HT(1A) mRNA levels were regulated in a complex manner in the different subfields of hippocampus. We conclude that both MR and GR play an integrated role in regulating 5-HT(1A) mRNA levels in hippocampus while having no effect on 5-HT(1B) mRNA levels under these conditions. (+info)
Leptin rapidly inhibits hypothalamic neuropeptide Y secretion and stimulates corticotropin-releasing hormone secretion in adrenalectomized mice.
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Leptin may rapidly inhibit food intake by altering the secretion of hypothalamic neuropeptides such as neuropeptide Y (NPY), a stimulator of food intake, and/or corticotropin-releasing hormone (CRH), an inhibitor of food intake. We measured concentrations of NPY and CRH in specific hypothalamic regions [i.e., arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial nucleus and dorsomedial nucleus] of 7- to 8-wk-old lean and ob/ob mice at 1 or 3 h after intracerebroventricular leptin administration. No rapid-onset effects of leptin on hypothalamic NPY or CRH concentrations were observed in intact mice. The addition of leptin to hypothalamic preparations from intact mice also did not alter NPY or CRH secretion. Glucocorticoids may oppose leptin actions. Consistent with this, leptin administration to adrenalectomized mice markedly reduced CRH concentrations in the ARC within 3 h after injection. This rapid reduction in CRH concentration in the ARC after leptin administration is more likely due to stimulated CRH release from this region than to decreased synthesis/transport from the PVN because leptin stimulates CRH synthesis in the PVN. Within 20 min after exposure to leptin, NPY secretion from hypothalamic preparations obtained from adrenalectomized mice was lowered by 27% and CRH secretion was elevated by 51%. The current study demonstrates that leptin rapidly influences the secretion of hypothalamic NPY and CRH and that these actions of leptin within the hypothalamus are restrained by the presence of endogenous corticosterone. (+info)
Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency.
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BACKGROUND: Glucocorticoids are essential for the normal development and functioning of the adrenal medulla. Whether adrenomedullary structure and function are normal in patients with congenital adrenal hyperplasia is not known. METHODS: We measured plasma and urinary catecholamines and plasma metanephrines in 38 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (25 children with the salt-wasting form and 13 with the simple virilizing form), 39 age-matched normal subjects, and 20 patients who had undergone bilateral adrenalectomy. Adrenal specimens obtained from three other patients with 21-hydroxylase deficiency who had undergone bilateral adrenalectomy and specimens obtained at autopsy from eight other patients were examined histologically. RESULTS: Plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were 40 to 80 percent lower in the patients with congenital adrenal hyperplasia than in the normal subjects (P<0.05), and the values were lowest in the patients with the most severe deficits in cortisol production. Urinary epinephrine excretion and plasma epinephrine concentrations were at or below the limit of detection of the assay in 8 (21 percent) of the patients with congenital adrenal hyperplasia and in 19 (95 percent) of the patients who had undergone adrenalectomy. In the group of patients with congenital adrenal hyperplasia, plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were approximately 50 percent lower in those who had been hospitalized for adrenal crises than in those who had not. In three patients with congenital adrenal hyperplasia who had undergone bilateral adrenalectomy, the formation of the adrenal medulla was incomplete, and electron-microscopical studies revealed a depletion of secretory vesicles in chromaffin cells. CONCLUSIONS: Congenital adrenal hyperplasia compromises both the development and the functioning of the adrenomedullary system. (+info)
Effect of steroid hormone deprivation on the expression of ecto-ATPase in distinct brain regions of female rats.
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Abundant evidence indicates that ATP and adenosine act as neurotransmitters or co-transmitters, influencing nerve cell physiology in various ways. Therefore, regulation of ATP-metabolizing enzymes is essential for the normal development and function of neuronal tissue. In the present study we have examined the effect of gonadal (OVX) or adrenal (ADX) steroid hormone deprivation on the activity and expression of synaptic membrane ecto-ATPase in three extrahypothalamic brain areas of female rats, primarily not associated with reproductive function. It was shown that OVX significantly increased ecto-ATPase activity and the relative abundance of this enzyme in the hippocampal (Hip) and caudate nucleus (CN), but not in brain stem (BS) membrane preparations. ADX was followed by an upregulation of the enzyme activity and its relative abundance in all the brain areas investigated. The highest enzyme activity and the most profound effects of OVX and ADX were detected in the CN. The results obtained indicate that ADX and OVX upregulate the expression of ecto-ATPase, potentiating the production of adenosine in synaptic cleft thus modulating the activity of numerous neurotransmitter systems in distinct areas of the CNS. (+info)
Thymic hyperplasia as a source of ectopic ACTH production.
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A 26 year-old man with suspected Cushing's disease underwent transsphenoidal exploration of the pituitary without any evidence of microadenoma or hyperplasia. Progressive hypercortisolism necessitated bilateral adrenalectomy. Postoperatively, skin pigmentation gradually developed with a marked elevation of plasma ACTH levels, and CT scanning uncovered a thymic mass. Following removal of the thymic mass, skin pigmentation disappeared and plasma ACTH levels fell to normal. The excised mass was found to be a benign thymic hyperplasia without epithelial or carcinoid tumor cells. However, gel chromatography showed that the thymic tissue extract contained high ACTH content comparable to that of ectopic ACTH-producing tumors with a major component corresponding to ACTH(1-39). Northern blot analysis and in situ hybridization revealed the expression of proopiomelanocortin transcripts in lymphocytes of thymic hyperplasia. This report suggests that lymphocytes in thymic hyperplasia are the most likely site of deregulated ACTH expression causing ectopic ACTH syndrome. (+info)
Adrenalectomy reverses obese phenotype and restores hypothalamic melanocortin tone in leptin-deficient ob/ob mice.
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In genetically obese leptin-deficient ob/ob mice, adrenalectomy reverses or attenuates the obese phenotype. Relative to lean controls, ob/ob mice also exhibit decreased hypothalamic proopiomelanocortin (POMC) mRNA and increased hypothalamic agouti-related peptide (AGRP) mRNA and neuropeptide Y (NPY) mRNA. It has been hypothesized that this profile of hypothalamic gene expression contributes to the obese phenotype caused by leptin deficiency. To assess if reversal of obese phenotype by adrenalectomy entails normalization of hypothalamic gene expression, male wild-type and ob/ob mice were adrenalectomized (with saline supplementation) or sham adrenalectomized at 2 months of age. Mice were sacrificed 2 weeks after adrenalectomy, during which time food intake and body weight were monitored daily. After sacrifice, hypothalamic gene expression was assessed by Northern blot analysis as well as in situ hybridization. In wild-type mice, adrenalectomy significantly decreased AGRP mRNA but did not significantly influence POMC or NPY mRNA. In ob/ob mice, adrenalectomy reduced the levels of plasma glucose, serum insulin and corticosterone, and food intake toward or below wild-type levels, and it restored hypothalamic POMC and AGRP mRNA but not NPY mRNA to wild-type levels. These studies suggest that adrenalectomy reverses or attenuates the obese phenotype in ob/ob mice, in part by restoring hypothalamic melanocortin tone toward wild-type levels. These studies also demonstrate that factors other than leptin may play a major role in regulating hypothalamic melanocortin function. (+info)